Elaiophyline derivatives, compositions containing them and the use thereof as anthelmintic agents

ABSTRACT

The invention relates to elaiophyline derivatives of the formula I ##STR1## in which R 1  and R 1&#39;  are identical or different and represent a radical of the formula II/or III ##STR2## in which R 2 , R 3 , R 4 , R 5  and R 7  have the meanings given. The invention furthermore relates to a process for the preparation of these elaiophyline derivatives and also the use of the lattere as medicaments, in particular as anthelmintically acting medicaments.

DESCRIPTION

Elaiophyline was first isolated over 25 years ago by Arcamone et al.(giorn. Microbiol. 7, 207, 1959) and later described by Arai under thename Azalomycin B. Kaiser et al. (Helv. Chim. Acta, 64 (1981), 407)isolated elaiophyline together with nigericin and the niphitricines Aand B from cultures of a strain of Streptomyces violaceoniger.

It has already been proposed (P 3,721,722.4) to employ elaiophyline asan anthelmintic, since in particular it displays a good action againstgastrointestinal tract strongylidae and lung worms, with which, aboveall, household animals and productive animals are infested.

It has now been found that by chemical derivatization of elaiophylinethe anthelmintic action can still be increased.

Several derivatives of elaiophyline are already known; however theirpharmacological spectrum of action is far from the anthelmintic actiondescribed here; these derivatives are mostly employed as ulcertherapeutics.

Several alkyl, alkenyl and alkynyl derivatives and also phenyl andfurylalkyl derivatives in the 11- and 11'-position of elaiophyline arealready known (Japanese Preliminary Published Application 61-36295,YOKURA et al.). The reduced and partly reduced semiacetals ofelaiophyline are also known, where the 6'-ring is opened at C11 or atC11 and C11' and also the tetraacetyl derivatives (3", 3"', 4",4"'-tetra-0-acetyl) of elaiophyline (see loc. cit. Kaiser et al.). Bothfrom the reduced semiacetals and also from the tetraacetyl derivatives,the compounds are already known in which the C--C double bonds of themacroiolide ring are completely hydrogenated (see Loc. cit. Kaier etal.).

The invention now relates to:

Elaiophyline derivatives of the formula I ##STR3## where the C--C doublebonds in the macrodiolide ring of the compound of the formula (I) canalso be hydrogenated and in which

R¹ is a radical of the formula II or III ##STR4## in which R² and R³ areidentical or different and denote hydrogen or a radical of the formulaIV or IV' ##STR5## in which n denotes 1 to 3 and

R⁶ denotes C₁ -C₁₅ -alkyl, C₂ -C₁₅ -alkenyl, C2-C15-alkynyl, C₃ -C₉-cycloalkyl, aryl or heteroaryl, where the aryl and heteroaryl radicalsare optionally substituted by halogen, nitro, cyano, hydroxyl, C₁ -C₄-alkyl or C₁ -C₄ -alkoxy and where for the case in which R³ is hydrogen,R² is also hydrogen,

or in which

R² and R³ are identical and denote C₁ -C₄ -alkyl, benzyl, allyl, MEM,MOM, SEM, trimethylsilyl, triethylsilyl, dimethylphenylsilyl,dimethylcyclohexylsilyl or dimethyl tertiary butylsilyl

or

R² and R³ denote sulfonates of the formula SO₂ R¹⁰

in which R¹⁰ denotes C₁ -C₁₀ -alkyl, phenyl or p-tolyl

or

R² and R³ represent a radical of the formula V or V' ##STR6## in which ndenotes 1 to 3

X denotes oxygen or sulfur

R¹² denotes C₁ -C₁₅ -alkyl, C₃ -C₉ -cycloalkyl, aryl, pyridyl, pyrimidylor pyrazinyl, where the aryl, pyridyl, pyrimidyl or pyrazinyl radicalsare optionally substituted by halogen, nitro, cyano or C₁ -C₄ -alkoxyand

Z denotes oxygen, --N--H or a radical --N--R¹² or --N--(CH₂)_(n) ^(--R)¹², where n and R¹² have the above-mentioned meanings

or in which R² and R³ together represent a radical of the formula VI##STR7## in which R⁸ and R⁹ are identical or different and denotehydrogen or unbranched C₁ -C₁₀ -alkyl or where

R⁸ and R⁹ represent an alkylene chain, which together with the carbonatom carrying it, forms a 5-, 6- or 7-membered ring

or in which

R² and R³, for the case in which R¹ is a radical of the formula II, areidentical and represent a radical of the formula VIII ##STR8## in whichX denotes oxygen or sulfur

or

R² and R³, for the case in which R¹ is a radical of the formula II,together represent a radical of the formula ##STR9## wherein X denotesoxygen or sulfur

and in which

R⁴, provided that R² and R³ are hydrogen, denotes hydrogen or, for thecase in which R² and R³ do not denote hydrogen, is hydrogen or a radicalof the formula IV or IV' ##STR10## in which n and R⁶ have theabovementioned meanings

and

R⁵ is hydrogen or a radical of the formula --(CH₂)n-R⁶

where

n and R⁶ have the abovementioned meanings

and in which

R⁷ denotes hydrogen or--provided that R², R³ and R⁴ do notsimultaneously denote hydrogen--forms a radical of the formula IV orIV'--as defined above

and in which

R^(1') has the same meaning as R¹, where the two radicals R¹ and R^(1')can be substituted both by identical --except for the radicals R⁴ and R⁵and for the case in which R² and R³ together form a radical of theformula VI--and different substituents, with the exception that when R¹is a radical of the formula II.in which R² and R³ form a radical of theformula VIII or in which R² and R³ together form a radical of theformula ##STR11## for R^(1') the radicals R² and R³ in the radical ofthe formula II or III are not simultaneously hydrogen, excludingelaiophyline itself, elaiophyline having a hydrogenated macrodiolidering, and also compounds of the formula I, wherein the macrodiolide ringis hydrogenated or unhydrogenated and in which R¹ and R^(1') areidentical or different and represent a radical of the formula II and/orIII, wherein R² and R³ denote hydrogen or acetyl and R⁴ and R⁵ or R⁷denote hydrogen and likewise also excluding the compounds of the formulaI in which the macrodiolide ring is unhydrogenated and wherein R¹ andR^(1') simultaneously represent a radical of the formula II, wherein R²,R³ and R⁴ denote hydrogen and wherein

R⁵ denotes C₁ -, C₂ -, C₄ -C₈, C₁₀ -or C₁₂ -alkyl, phenyl C₁ -C₃ -alkyl,para-methoxy-phenyl-methyl, cyclohexylmethyl, C₄ -alkenyl or C₃-alkynyl.

The invention relates in particular to elaiophyline derivatives of theformula I, where the C-C double bonds in the macrodiolide ring of thecompound of the formula I can also be hydrogenated and in which R¹ is aradical of the formula II or III, in which

R² and R³ are identical or different and denote hydrogen or a radical ofthe formula IV or IV'

in which

n denotes 1 to 3 and

R⁶ denotes C₁ -C₅ -alkyl, C₂ -C₅ -alkenyl, C₂ -C₆

alkynyl, C₃ -C₆ -cycloalkyl, phenyl or furyl or thienyl, where thephenyl, furyl and thienyl radicals are optionally substituted byhalogen, nitro, cyano, hydroxyl, C₁ -C₄ -alkyl or C₁ -C₄ -alkoxy andwhere, for the case in which R³ is hydrogen, R² is also hydrogen,

or in which

R² and R³ are identical and denote MEM, MOM, SEM, trimethylsilyl,triethylsilyl, dimethylphenylsilyl, dimethylcyclohexylsilyl or dimethyltertiary butylsilyl

or

R² and R³ denote sulfonates of the formula SO₂ R¹⁰,

in which

R¹⁰ denotes C₁ -C₄ -alkyl, phenyl or p-tolyl

or

R² and R³ represent a radical of the formula V or V'

in which

n denotes 1,

X denotes oxygen,

R¹² denotes C₁ -C₄ -alkyl, C₃ -C₆ -cycloalkyl or aryl, where the arylradical is optionally substituted by halogen, nitro, cyano or C₁ -C₄-alkoxy and

Z denotes oxygen or --N--H or in which

R² and R³ together represent a radical of the formula VI

in which

R⁸ and R⁹ are identical or different and denote hydrogen or unbranchedC₁ -C₄ -alkyl or where

R⁸ and R⁹ represent an alkylene chain which, together with the carbonatom carrying it forms a 5- or 6-membered ring

or in which

R² and R³, for the case in which R¹ is a radical of the formula II, areidentical and represent a radical of the formula VIII,

in which

X denotes oxygen

or

R² and R³, for the case in which R¹ is a radical of the formula II,together represent a radical of the formula ##STR12## in which X denotesoxygen

and in which

R⁴, provided R² and R³ are hydrogen, denotes hydrogen or, for the casein which R² and R³ do not denote hydrogen, is hydrogen or a radical ofthe formula IV or IV',

in which

n is 1 to 3 and R⁶ has the abovementioned meanings,

and

R⁵ is hydrogen or a radical of the formula--(CH₂)n--R⁶

where

n is 1 to 3 and R⁶ has the abovementioned meanings

and in which

R⁷ denotes hydrogen or--provided R², R³ and R⁴ do not simultaneouslydenote hydrogen--forms a radical of the formula IV or IV' as definedabove

and in which

R^(1') has the same meaning as R¹, in which the two radicals R¹ andR^(1') can be substituted both by identical substituents andalso--except for the radicals R⁴ and R⁵ and for the case in which R² andR³ together form a radical of the formula VI--different substituents,with the exception that when R¹ is a radical of the formula II :n whichR² and R³ form a radical of the formula VIII or in which R² and R³together form a radical of theformula ##STR13## for R^(1') the radicalsR² and R³ in the radical of the formula II or III are not simultaneouslyhydrogen, excluding elaiophyline itself, elaiophyline having ahydrogenated macrodiolide ring, and also compounds of the formula I, inwhich the macrodiolide ring is hydrogenated or unhydrogenated and inwhich R¹ and R^(1') are identical or different and represent a radicalof the formula II and/or III, in which R² and R³ denote hydrogen oracetyl and R⁴ and R⁵ or R⁷ denote hydrogen and likewise also excludingthe compounds of the.formula I, in which the macrodiolide ring isunhydrogenated and in which R¹ and R^(1') simultaneously represent aradical of the formula II, in which R², R³ and R⁴ denote hydrogen and inwhich

R⁵ denotes C₁ -, C₂ -, C₄ -C₅ -alkyl, phenyl-C₁ -C₃ -alkyl,para-methoxy-phenyl-methyl, cyclohexylmethyl, C₄ -alkenyl or C₃-alkynyl.

Elaiophyline derivatives of the formula I are particularly preferredwhere the C--C double bonds in the macrodiolide ring of the compound ofthe formula I can also be hydrogenated and in which R¹ is a radical ofthe formula II or III, in which

R² and R³ are identical or different and denote hydrogen or a radical ofthe formula IV or IV', in which

n denotes 1,

R⁶ denotes C₁ -C₅ -alkyl, cyclohexyl, phenyl, furyl or thienyl, in whichthe phenyl, furyl, and thienyl radicals are optionally substituted withfluorine, chlorine or bromine and where, for the case in which R³ ishydrogen, R² is also hydrogen,

or in which

R² and R³ are identical and denote MEM, MOM, SEM, trimethylsilyl,triethylsilyl, dimethylphenylsilyl, dimethylcyclohexylsilyl or dimethyltertiary butylsilyl

or

R² and R³ denote sulfonates of the formula SO₂ R¹⁰

in which

R¹⁰ denotes methyl, phenyl or p-tolyl

or

R² and R³ represent a radical of the formula V or V',

in which

n denotes 1

X denotes oxygen

R¹² denotes cyclohexyl or aryl, where the aryl radical is optionallysubstituted by halogen, nitro, cyano or C₁ -C₄ -alkoxy and

Z denotes oxygen or -N-H,

or in which

H R² and R³ together represent a radical of the formula VI

in which

R⁸ and R⁹ are identical or different and denote hydrogen or unbranchedC₁ -C₄ -alkyl or where

R⁸ and R⁹ represent an alkylene chain which, together with the carbonatom carrying it forms a 5- or 6-membered ring

or in which

R² and R³, for the case in which R¹ is a radical of the formula II, areidentical and represent a radical of the formula VIII

in which

X denotes oxygen

or

R² and R³, for the case in which R¹ is a radical of the formula II,together represent a radical of the formula ##STR14## in which X denotesoxygen

and in which

R⁴, provided R² and R³ are hydrogen, denotes hydrogen or, for the casein which R² and R³ do not denote hydrogen, is hydrogen or a radical ofthe formula IV or IV',

n is 1 and R⁶ has the abovementioned meanings

and

R⁵ is hydrogen or a radical of the formula -(CH₂)_(n) -R⁶

in which

n is 1 and R⁶ has the abovementioned meanings and in which

R⁷ denotes hydrogen or--provided R2, R³ and R⁴ do not simultaneouslydenote hydrogen--forms a radical of the formula IV or IV'--as definedabove--

and in which

R^(1') has the same meaning as R¹, where the two radicals R¹ and R^(1')can be substituted both with identical substituents and also--except forthe radicals R⁴ and R⁵ and for the case in which R² and R³ together forma radical of the formula VI--and likewise also different substituents,with the exception that when R¹ is a radical of the formula II, in whichR² and R³ form a radical of the formula VIII or in which R² and R³together form a radical of the formula ##STR15## for R^(1') the radicalsR² and R³ in the radical of the formula II or III are not simultaneouslyhydrogen, excluding elaiophyline itsself, elaiophyline having ahydrogenated macrodiolide ring, and also compounds of the formula I, inwhich the macrodiolide ring is hydrogenated or unhydrogenated and inwhich R¹ and R^(1') are identical or different and represent a radicalof the formula II and/or III, in which R² and R³ denote hydrogen oracetyl and R⁴ and R⁵ or R⁷ denote hydrogen and likewise also excludingthe compounds of the formula I in which the macrodiolide ring is nothydrogenated and in which R¹ and R^(1') simultaneously represent aradical of the formula II, in which R², R³ and R⁴ denote hydrogen and inwhich R⁵ denotes C₁ -C₂ - or C₄ -C₅ -alkyl, phenylmethyl orcyclohexylmethyl.

The invention furthermore relates to elaiophyline derivatives of theformula I as claimed in claim 1, but including elaiophyline having ahydrogenated macrodiolide ring, and also compounds of the formula I, inwhich the macrodiolide ring is hydrogenated or unhydrogenated and inwhich R¹ and R^(1') are identical or different and represent a radicalof the formula II and/or III, in which R² and R³ denote hydrogen oracetyl and R⁴ and R⁵ or R⁷ denote hydrogen and likewise also includingthe compounds of the formula I, in which the macrodiolide ring is nothydrogenated and in which R¹ and R^(1') simultaneously represent aradical of the formula II, in which R², R³ and R⁴ denote hydrogen and inwhich

R⁵ denotes C₁ -, C₂ -, C₄ -C₈, C₁₀ - or C₁₂ -alkyl, phenylR C₁ -C₃-alkyl, para-methoxy-phenyl-methyl, cyclohexylmethyl, C₄ -alkenyl or C₃-alkynyl,

for use as anthelmintics.

Preferred elaiophyline derivatives are those of the formula I, asclaimed in claim 2, but including elaiophyline having a hydrogenatedmacrodiolide ring, and also compounds of the formula I in which themacrodiolide ring is hydrogenated or unhydrogenated and in which R¹ andR^(1') are identical or different and represent a radical of the formulaII and/or III, in which R² and R³ denote hydrogen or acetyl and R⁴ andR⁵ or R⁷ denote hydrogen and likewise also including the compounds ofthe formula I in which the macrodiolide ring is not hydrogenated and inwhich

R¹ and R^(1') simultaneously represent a radical of the formula II, inwhich R², R³ and R⁴ denote hydrogen and in which

R⁵ denotes C₁ -, C₂ -, C₄ -C₅ -alkyl, phenyl-C₁ -C₃ -alkyl,para-methoxy-phenyl-methyl, cyclohexylmethyl, C₄ -alkenyl or C₃-alkynyl,

for use as anthelmintics.

Particularly preferred elaiophyline derivatives are those of the formula1, as claimed in claim 3, but including elaiophyline having ahydrogenated macrodiolide ring, and also compounds of the formula I, inwhich the macrodiolide ring is hydrogenated or unhydrogenated and inwhich R¹ and R^(1') are identical or different and represent a radicalof the formula II and/or III, in which R² and R³ denote hydrogen oracetyl and R⁴ and R⁵ or R⁷ denotes hydrogen and likewise also includingthe compounds of the formula I, in which the macrodiolide ring is nothydrogenated and in which R¹ and R^(1') simultaneously represent aradical of the.formula II, in which R², R³ and R⁴ denote hydrogen and inwhich

R⁵ denotes C₁ -C₂ -, C₄ -C₅ -alkyl, phenylmethyl or cyclohexylmethyl,

for use as anthelmintics.

The invention likewise relates to a process for the preparation ofelaiophyline derivatives of the formula I wherein

(a) elaiophyline (formula I: R¹ =R^(1') =II, R² =R³ =R⁴ =R⁵ =H) or acompound of the formula I in which R¹ and R^(1') are identical ordifferent and represent a radical of the formula II and/or III, in whichR², R³ and R⁴ have the abovementioned meanings and R⁵ or R⁷, except forhydrogen, have the abovementioned meanings, is reacted with a compoundof the formula IX or IX'. ##STR16## in which n and R⁶ have the meaningsmentioned above for formula IV or IV' and Q denotes chloride, bromide,an imidazolide or an acid anhydride, by means of which compounds of theformula I are obtained, in which R¹ and R^(1') are identical ordifferent and represent a radical of the formula II and/or III, in whichR² and R³ are identical or different and represent a radical of theformula IV or IV', as defined above, and in which R⁴ and R⁵ or R⁷ remainunchanged compared to the starting compound, or wherein

(b) an elaiophyline derivative of the formula I in which R¹ and R^(1')are identical or different and represent a radical of the formula IIand/or III, in which R², R³ and R⁴ have the abovementioned meanings andR⁵ or R⁷, except for hydrogen, have the abovementioned meanings, arereacted with a compound selected from: C₁ -C₄ -alkyl, benzyl, or allylchloride, bromide or iodide, or MEM chloride, MOM chloride or SEMchloride, trimethylsilyl-, triethylsilyl-, dimethylphenylsilyl-,dimethylcyclohexylsilyl- or dimethyl tertiary butylsilyl chloride,sulfonyl halides of the formula Y--SO₂ R¹⁰, in which Y denotes chlorine,bromine or iodine and R¹⁰ has the abovementioned meanings, isocyanatesof the formula

    0═C═N--R.sup.12 or

    0═C═N--(CH.sub.2).sub.n --R.sup.12, isothiocyanates of the formula

    S═C═N--R.sup.12 or

    S═C═N--(CH.sub.2).sub.n --R.sup.12, carbamoyl halides of the formula

    Y--CO--N--[(CH.sub.2).sub.n --R.sup.12 ].sub.2, thiocarbamoyl halides of the formula

Y--CS--N--CR¹²)₂ or

    Y--CS--N--[(CH.sub.2).sub.n --R.sup.12 ].sub.2,

where n and R¹² have the meanings given above for formula V or V' and Ydenotes chlorine or bromine, by means of which compounds of the formulaI are obtained, in which R¹ and R^(1') are identical or different andrepresent a radical of the formula II and/or III, in which R² and R³ areidentical and represent a C₁ -C₄ alkyl, benzyl, allyl, MEM, MOM, SEM,trimethylsilyl, triethylsilyl, dimethylphenylsilyl,dimethylcyclohexylsilyl or dimethyl tertiary butylsilyl radical or asulfonate of the formula SO₂ R¹⁰ or a radical of the formula V or V',where R¹⁰ and the formulae V and V' have the abovementioned meanings andin which R⁴ and R⁵ or R⁷ are unchanged compared to the startingcompound, or wherein

(c) elaiophyline (formula I: R¹ =R^(1') =II, R² =R³ =R⁴ =R⁵ =H) isreacted with an aldehyde/ketone of the formula X ##STR17## or with aketal of the formula XI ##STR18## in which denotes methyl or ethyl andR⁸ and R⁹ have the abovementioned meanings, by means of which compoundsof the formula I are obtained, in which R¹ and R^(1') are identical andrepresent a radical of the formula II, in which R² and R³ togetherrepresent a radical of the formula VI, as defined above, or wherein

(d) elaiophyline (formula I: R¹ =R^(1') =II, R² =R³ =R⁴ = R⁵ =H) or acompound of the formula I, in which R¹ and R^(1') are identical ordifferent and represent a radical of the formula II, in which R², R³ andR⁴ have the abovementioned meanings and R⁵, except for hydrogen, has theabovementioned meanings, are reacted if appropriate in the presence of abase with carbonyldiimidazole or thiocarbonyldiimidazole, by means ofwhich compounds of the formula I are obtained, in which R¹ and R^(1')are identical or different and represent a radical of the formula II, inwhich R² and R³ are identical and represent a radical of the formulaVIII, as defined above, or in which R² and R³ together represent aradical of the formula ##STR19## as defined above, and in which R⁴ andR⁵ are unchanged compared to the starting compound, or wherein (e) acompound of the formula I, in which R¹ and R^(1') are identical ordifferent and represent a radical of the formula II and/or III, in whichR² and R³, except for hydrogen, have the abovementioned meanings andin.which R⁴ denotes hydrogen and R⁵ or R⁷, except for hydrogen, has theabovementioned meanings, is reacted according to process variation a)with a compound of the formula IX or IX', as defined under a), by meansof which compounds of the formula I are obtained, in which R¹ and R^(1')are identical or different and represent a radical of the formula IIand/or III, in which R² and R³, except for hydrogen, have theabovementioned meanings and R⁴ denotes a radical of the formula IV orIV', as defined above, in which R⁴ in R1' is identical with R⁴ in R¹ andin which R⁵ or R⁷ is unchanged compared to the starting compound, orwherein

(f) elaiophyline or a compound of the formula I, in which R¹ and R^(1')are identical or different and represent a radical of the formula II, inwhich R², R³ and R⁴ have the abovementioned meanings and in which R⁵denotes hydrogen, is preferably reacted in the presence of a Lewis acidwith an alcohol of the formula HO-(CH₂)n-R⁶ in which n and R⁶ have theabovementioned meanings, by means cf which compounds of the formula Iare obtained, in which R¹ and R^(1') are identical or different andrepresent a radical of the formula II, in which R² and R³ and R⁴ havethe abovementioned meanings and R⁵ in the radicals R¹ and R^(1') isidentical and represents a radical of the formula--(CH₂)_(n) --R⁶ or--R⁶, as defined above, or wherein

(g) elaiophyline (formula I: R¹ =R^(1') =II, R² =R³ =R⁴ =R⁵ =H) or acompound of the formula I in which R¹ and R^(1') are identical ordifferent and represent a radical of the formula II, wherein R², R³ andR⁴ have the abovementioned meanings and R⁵ is hydrogen, where thesubstituents of the formula VIII and also the carbonyl and thiocarbonylradicals are excluded for R² and R³, is reduced, by means of which acompound of the formula I is obtained, in which R¹ and/or R^(1') is aradical of the formula III, in which R², R³ and R⁴ have theabovementioned meanings and R⁷ denotes hydrogen, or wherein

(h) a compound of the formula I, in which R¹ and/or R^(1') is a radicalof the formula III in which R² R³ and R⁴ have the abovementionedmeanings and R⁷ denotes hydrogen, is reacted according to processvariation (a) with a compound of the formula IX or IX', as defined inprocess variation a), to give a compound of the formula I, in which R¹and/or R^(1') is a radical of the formula III, in which R², R³ and R⁴have the abovementioned meanings or, provided that R² and/or R³ and/orR⁴ denoted hydrogen before the reaction, R² and/or R³ and/or R⁴ afterthe reaction have the meaning of R⁷, and in which R⁷ is a radical of theformula IV or IV', as defined above, or wherein

(i) a compound of the formula I, in which R¹ and/or R^(1') is a radicalof the formula II and/or III, in which R², R³, R⁴ and R⁵ or R⁷ have theabovementioned meanings, is hydrogenated, by means of which ahydrogenated com

pound of the formula I is obtained, in which R¹ and/or R^(1') is aradical of the formula II and/or III, in which R², R³, R⁴ and R⁵ or R⁷have the abovementioned meanings.

Aryl is taken to mean aromatic hydrocarbons, in particular phenyl andnaphthyl and heteroaryl is taken to mean heteroaromatic hydrocarbons, inparticular thiophene and furan, but also pyridine, pyrimidine andpyrazine.

Halogens are taken to mean fluorine, chlorine, bromine and iodine, MEMis taken to mean methoxyethoxymethyl, MOM is taken to mean methoxymethyland SEM is taken to mean β-trimethylsilylethoxymethyl.

The macrodiolide ring of elaiophyline can--independently of the type ofsubstituents R¹ and R^(1') --be hydrogenated or unhydrogenated.

The substituents R¹ and R^(1') can be both identical and different, i.e.it is possible both that R¹ and R^(1') represent a radical of theformula II or III and also that R¹ represents a radical of the formulaII and R^(1') represents a radical of the formula III (the reverse: R¹=a radical of the formula III and R^(1') =a radical of the formula IIis, based on the symmetry of the molecule, identical with R¹ =II andR^(1') =III). Likewise it is possible--with H a few exceptions - tobuild different R², R³, R⁴, R⁵ or R⁷ radicals into the radicals R¹ andR^(1'). This is independent of whether the radicals R¹ and R^(1') nowboth represent a radical of the formula II or III or are different, i.e.R¹ represents a radical of the formula II and R^(1') represents aradical of the formula III. However, if R¹ and R^(1') represent aradical of the formula II, then R⁵ is the same in both substituents R¹and R^(1')

The substituent R⁴ is always identical in the radicals R¹ and R^(1') andcan then only be different from hydrogen when the substituents R² and R³are also different from hydrogen. Likewise, R² can then only bedifferent from hydrogen when R³ is also different from hydrogen.

In the following, the processes (a) to (h), which make it possible toprepare the different substituted elaiophyline derivatives, are moreclosely described.

With the aid of process variation a), the hydroxyl groups in the 3"--or3"'--position and 4"--or 4"'--position of elaiophyline can beesterified. Since the reaction rate of the esterification in the 3"--or3"'--position --i.e. for the R³ derivative--is greater than that of theesterification in the 4"--or 4"'--position, the possibility presentsitself to provide both identical and also different substituents for R²and R³.Likewise, it is possible in this manner to build different R²and/or R³ radicals into the substituents R¹ and R^(1'). For example,elaiophyline--or its homologue having a hydrogenated macrodiolidering--can be monoacetylated with a reagent A (for example in the3"--position) and then converted with a reagent B--into a 3"', 4",4"'--tri-0-acetyl(B)--3"-0-acetyl(A)-derivative. In a similar manner, itis completely possible to introduce four different substituents into the3"-, 3"'-, 4"- and 4"'-position in the molecule.

At relatively high temperatures and/or sufficiently long reaction times,the OH group in the 9- or 9'-position is also esterified. This, however,also denotes that an esterification in the 9- or 9'-position is onlypossible after previous esterification of the OH groups in the 3"/3"'-and 4"/4"'-position. In this manner, for example, the OH groups in the3"/3"'- and 4"/4"'-position can therefore be initially esterified andthen, if appropriate after isolating and purifying the product, the OHgroup in the 9- and/or 9'-position can then be esterified in a secondreaction (process variation e) corresponding to process variation a.

In process variation a), a procedure is thus best used in whichelaiophyline (R¹ =R^(1') =II; R², R³, R⁴ or R⁵ =H) or a compound of theformula I, in which R¹ and R1' are identical or different and representa radical of the formula II and/or III, in which R2, R³ and R⁴ have theabovementioned meanings and R⁵ or R7, except for hydrogen, have theabovementioned meanings, is reacted in equimolar amounts or in up to a50-fold excess, if appropriate in an inert, aprotic solvent such aschloroform, methylene chloride, tetrahydrofuran (THF), ethyl acetate ordioxane, with a compound of the formula IX or IX' until completion ofthe reaction, if appropriate in the presence of a base, preferablypyridine.

The reaction temperatures in this case lie between -70° C. and +100° C.,preferably when using a solvent between the solidification point and theboiling point of the solvent, in particular between -70° C. and +40° C.The reaction times are 1 to 180 hours, preferably 1 to 48 hours,particularly preferably 1 to 8 hours. The completion of the reaction canbe determined, for example, by means of thin layer chromatography (TLCchecking).

The elaiophyline required as the starting substance can be prepared, forexample, according to the process described in the German PatentApplication P 3,721,722.4. Here, elaiophyline is produced as thefermentation product of cultures of the strains Streptomycesviolaceoniger DSM 4137 or Streptomyces parvulus DSM 3816.

The starting compounds for process variation a), the compounds of theformula IX and/or IX', can be prepared, unless commercially available,in a simple manner by processes known in the literature. For example,the acid chlorides are obtained by reaction of the correspondingcarboxylic acid with thionyl chloride, PCL₃ or PCL₅. Such processes are,for example, described in Gattermann/Wieland, "Die Praxis desOrganischen Chemikers" ("The Practice of Organic Chemists"), 43rdedition, Walter de Gruyter, Berlin, New York 1982, page 303 et seq.

In process variation (b), a procedure is thus best used in whichelaiophyline or an elaiophyline derivative is reacted in equimolaramounts or in an excess of up to 50-fold with a compound which isselected from:

C₁ -C₄ -alkyl, benzyl or allyl chloride, bromide or iodide, or MEMchloride, MOM chloride or SEM chloride, trimethyl- silyl-,triethylsilyl-, dimethylphenylsilyl-, dimethyl- cyclohexylsilyl- ordimethyl tert.-butylsilyl chloride, H sulfonyl halides of the formulaY-SO₂ R¹⁰, isocyanates of the formula 0=2 or 0=C=N--(CH₂)_(n) --R¹²,isothiocyanates of the formula or S=C=N-(CH₂)_(n) --R¹², carbamoylhalides of the formula Y-CO-N-(R¹²)₂ or Y-CO-N-[(CH₂)_(n) --R¹² ]₂,thiocarbamoyl halides of the formula Y-CS-N-(R¹²)₂ or Y-CS-N-[(CH₂)_(n)--R¹² ]₂.

If appropriate, this reaction can also take place with the addition of abase. Suitable bases are, for example, triethylamine, pyridine orlutidine. A variation of process b) consists of working in a suitable,preferably inert solvent such as chloroform, methylene chloride, THF,ethyl acetate or dioxane. The excess of the abovementioned compounds canalso be up to a 50-fold amount here.

The reaction temperatures here lie between -70° C. and +100° C,preferably when using a solvent between the solidifying point and theboiling point of the solvent, in particular between -70° C and -40° C.The reaction times are to 180 hours, preferably 1 to 48 hours,particularly preferably 1 to 8 hours. The completion of the reactioncan, for example, be determined by means of TLC checking.

The starting compounds for process variation b) can be prepared, unlesscommercially available, in a simple manner by processes known in theliterature. For example, the sulfonyl halides of the formula Y-SO₂ R¹⁰is obtained by radical reaction of alkanes with chlorine and SO₂ or byhalogenation of aromatics with a halogenosulfonic acid Y--SO₃ H. Theisocyanates, isothiocyanates, carbamoyl halides and thiocarbamoylhalides are obtained by processes known from the literature such as aredescribed, for example, in Houben-Weyl, 4th edition, Georg Thieme VerlagStuttgart (1983), Volume E4.

With the aid of process variation c), the hydroxyl groups in the3"-/3"'-position and 4"-/4"'-position of elaiophyline can be acetalatedwith radicals R² and R³, which together represent a radical of theformula VI.

In process variation (c), a procedure is thus best used in whichelaiophyline is reacted in excess with a compound of the formula X or XIuntil completion of the reaction, if appropriate in the presence of aLewis acid such as ZnCL₂, ZnBr₂, FeCL₃, CuSO₄ or CuCL₂. A variation ofprocess b) consists of working in a suitable, aprotic solvent such aschloroform, methylene chloride, THF, ethyl acetate or dioxane. An excessof X or XI can also be used here.

The reaction temperatures here lie between -20° C and +100° C,preferably when using a solvent between room temperature and the boilingpoint of the solvent, in particular between 20° C. and 100° C. Thereaction times are 1 to 50 hours, preferably 1 to 12 hours. Thecompletion of the reaction can be determined, for example, by means ofTLC checking.

The starting compounds for process variation c), the compounds of theformula X and/or XI, can be prepared, unless commercially available, ina simple manner by processes known from the literature. For example, thealdehydes of the formula X are obtained by oxidation of primary alcoholsor by reduction of carbonyl derivatives, for example with complexhydrides or by reduction of carboxyl chlorides (additional examples forthe synthesis of aldehydes, ketones and acetals or ketals can be foundin Organikum, Organisch Chemisches Praktikum, 15th edition, VEBDeutscher Verlag der Wissenschaften, Berlin 1976, Method Index, Acetals,Ketals, Aldehydes, Ketones, page 819 et seq.).

With the aid of process variation d), the hydroxyl groups in the3"-/3"'-position and 4"-/4"'-position of elaiophyline can be convertedinto the OR² -/OR³ - derivatives, in which R² and/or R³ represents acarbonylimidazolide, thiocarbonylimidazolide or together represent acarbonyl or thiocarbonyl radical. The reaction can be controlled inwhich, for example, the radical R¹ and R^(1') are identical and thesubstituents R² and R³ are also identical and denote carbonyl orthiocarbonylimidazole. Likewise, the reaction can, however, also becontrolled in which in the radical R¹ the substituents R² and R³represent a carbonyl or thiocarbonyl radical and in the radical R^(1')the L substituents R² and R³ are identical and denote carbonyl orthioncarbonylimidazole. This reaction can be influenced, for example, bya suitable variation of the mixing ratios of the starting substance orby the temperature control of the reaction. Thus, for example, thecorresponding carbonyls or thiocarbonyls are formed from the carbonyl orthiocarbonylimidazolides in greater quantities at higher temperatures.

In process variation (d), a procedure is thus best used in whichelaiophyline or an elaiophyline derivative is reacted in equimolaramounts or in an excess of up to 5-fold with carbonyldiimidazole orthiocarbonyldiimidazole until completion of the reaction, if appropriatein the presence of a base such as pyridine. A variation of the processconsists of working in a suitable aprotic solvent such as chloroform,methylene chloride, THF, ethyl acetate or dioxane. An excess ofcarbonyldiimidazole or thiocarbonyldiimidazole, which can be up to abouta 5-fold amount, can also be used here. The reaction temperatures inthis case are between 0° C. and 100° C, preferably when using a solventbetween the solidifying point and the boiling point of the solvent, inparticular between 0° C. and 40° C. The reaction times are 1 to 48hours, preferably 1 to 24 hours. The completion of the reaction can bedetermined, for example, by means of TLC checking.

The starting compounds for process variation (d), carbonyldiimidazole orthiocarbonyldiimidazole, are commercially available.

With the aid of process variation (e), the OH groups in the 9- and/or9'-position can be esterified, as already described above. Aprerequisite for an esterification in this position is that the protonsof the OH-groups in the 1"-/4"--position and 3"'-/4"'-position arealready substituted. Otherwise, first these OH-groups would react withthe acylating reagents and only later--in a suitable excess--those inthe 9-/9'-position. The substituents R² and R³ could, for example, beintroduced into the molecule in one of the described process variations(a) to (d). All process parameters for variation (e) are to be inferredfrom the description of variation (a). In some cases particularly whenR² /R³ and R⁴ hould represent different substituents--it is expedient,in connection with one of the process variations (a) to (d), to isolateand if necessary to purify the reaction products before it is reactedfurther according to process variation (e).

The required starting compounds of the formula IX and IX' are eithercommercially available or can be synthesized simply in the mannerdescribed for variation (a).

With process variation f), the substituent R⁵ can be introduced into themolecule. Here, this reaction can be carried out selectively on theOH-group of the C₁₁ -/C₁₁ '-position, independently of the type of thesubstituents R², R³ and R⁴ In this process variation, a procedure isthus best used in which elaiophyline or a suitable R², R³ or R⁴derivative is reacted with an excess of an alcohol of the formulaHO-(CH₂)_(n) -R⁶ in the presence of catalytic amounts of a Lewis aciduntil completion of the reaction. A variation of the process consists inworking in a suitable solvent such as chloroform, methylene chloride,THF, ethyl acetate or dioxane. Suitable Lewis acids are, for example,halides of copper, iron or lithium, in particular CuCL₂, FeCL₃ or-LiBr.

The concentration of the Lewis acid--in relation to L elaiophyline orthe elaiophyline derivative--is 0.1 to 5% by weight, preferably 0.5 to1% by weight. The reaction temperatures here lie between -40° C. and+100° C., in particular between 0° C. and 30° C., preferably when usinga solvent between the solidifying point and the boiling point of thesolvent, in particular between 0° C. and 30° C. The reaction times are 1to 180 minutes, preferably 5 to 60 minutes. The completion of thereaction can be determined, for example, by means of thin layerchromatography.

With the aid of process variation (g), the semiacetal of elaiophylinecan be reduced, by means of which the 6-ring 35 is opened at C₁₁ or C₁₁'. This reduction can only be carried out, however, when R⁵ denoteshydrogen. With the exception of the case in which R² and R³ represent acarbonylimidazolide, a thiocarbonylimidazolide or together represent acarbonyl or thiocarbonyl radical, the type of the remaining substituentsR², R³ and R⁴ is uncritical for the reduction.

In process variation (g), a procedure is thus best used in whichelaiophyline or an elaiophyline derivative obtainable by one of theprocess variations a) to f) or i) is reduced using a boranate of analkali metal or an alkaline earth metal, preferably using NaBH₄ in asolvent, preferably in an alcohol such as isopropanol or in an ethersuch as THF. Suitable methods are described, for example, inHouben-Weyl, 4th edition, Volume 4/1d, G. Thieme Verlag, Stuttgart 1981.

The reaction temperatures here lie between -70° C. and 100° C.,preferably between the solidifying point and the boiling point of thesolvent, in particular between -20° C. and +20° C. The reaction timesare 1 to 60 hours, preferably 5 to 20 hours. The completion of thereaction can be determined, for example, by means of TLC checking.

By means of process variation h) the hydroxyl groups at C11/C11' andC15/15' can be esterified. Here, process variation a) again comes intouse, which at the same time means, however, that before theesterification of the C15/C15'- and C11/ C11'-OH-groups, the OH-groupsin the 3"/3"'- and 2"/2"'-position and if appropriate also those in the9/9'-position first would have to be esterified, since otherwise theseOH-groups would be esterified in one o step with the C15/15'-andC11/11'-OH-groups.

All process parameters for variation h) are to be inferred from thedescription of variation a). In some cases, particularly when R², R³, R⁴and R⁷ represent different substituents, it is expedient in connectionwith one or more of the process variations (a) to (e) and (g) to isolateand if necessary, to purify the reaction products before the desiredproduct is reacted further according to process variation (h).

With the aid of process variation (i), the C-C double bonds of themacrodiolide ring can be hydrogenated. This hydrogenation can take placeboth before and after the reactions according to one or more of theprocess variations (a) to (h). Provided that the desired elaiophylinederivative contains unsaturated or reducible R², R³, R⁴, R⁵ or R⁷substituents, the hydrogenation of the macrodiolide ring expedientlytakes place before the attachment of the corresponding unsaturatedsubstituent(s).

In process variation (i), a procedure is thus best used in which theelaiophyline or elaiophyline derivative to be hydrogenated, preferablydissolved in a solvent such as methanol, ethanol, isopropanol or ethylacetate, or a mixture of these solvents or an aqueous mixture of thesesolvents, is reacted with hydrogen in the presence of a customaryhydrogenation catalyst according to processes known from the literature.Customary hydrogenation catalysts are, for example, elements of the 8thgroup such as 20 platinum, palladium and also nickel, which are mostlyapplied to activated charcoal, silica or alumina supports, for example,for the purpose of increasing the reactive surface. If the reaction iscarried out in an absolute primary alcohol as the solvent, then inaddition to a hydrogenation of the C=C double bonds, a ketalization tothe C_(11/) C₁₁ '-di-O-alkylene is also obtained.

According to the catalyst used, the reaction can be carried out bothwithout and with excess hydrogen pressure, for example up to 1atmosphere. The reaction temperatures are between 0° C. and 40° C.,preferably at room temperature. The reaction times are dependent on thebatch size and the concentration of the compound to be reduced. Suchhydrogenation processes are described, for example, in Organikum,Organisch Chemisches Grundpraktikum, 15th edition, VEB Deutscher Verlagder Wissenschaften, Berlin, 1976, pages 359-371.

The purification, isolation and working up of the substances takes placeby customary methods; for example the reaction products can be purifiedby chromatography on polar support materials such as silica gel or®Sephadex LH 20 using solvents such as lower alkanols such as methanolor chloroform or ethyl acetate or methanol/chloroform mixtures, but alsoby extraction methods such as liquid/liquid extraction or solid/liquidextraction or by crystallization.

The derivatives of elaiophyline show anthelmintic action, in particularagainst Haemonchus, Trichostrongylus, Ostertagia, Cooperia, Chabertia,Strongyloides, Oesophagostomum, Hygostrongylus, Ancylostoma, Ascaris andHeterakis. The activity towards gastrointestinal tract strongylidae andlung worms, with which household and productive animals, above all, areinfested, is particularly marked.

The elaiophyline derivatives can fundamentally be administered as asubstance per se. Use in a mixture with a suitable carrier material ispreferred. The customary feedstuff mixtures can be used as carriermaterials.

The invention is further illustrated in the following examples.Percentage data relate to the weight and mixture ratios in liquidsrelate to the volume, when no other data have been given.

EXAMPLES General process instructions Process

1 mmol of macrodiolide of the elaiophyline type (this is taken to meancompounds of the formula I in which the macrodiolide ring ishydrogenated or unhydrogenated) are dissolved in 10 ml of chloroform and10 ml of pyridine and stirred with the appropriate carboxylic acidderivatives. The excess of carboxylic acid derivative is decomposedusing 50 ml of water. The product is transferred into the organic phaseby extracting three times with ethyl acetate. The organic phase iswashed with 0.1 N hydrochloric acid and water, dried over sodium sulfateand concentrated in vacuo. By chromatography on 100 g of silica gelusing a linear gradient ethyl acetate: hexane/1:5 in ethyl acetate(about 5 liters), the corresponding compounds are obtained (see Table 1and 2).

Process 2

1 mmol of macrodiolide of the elaiophyline type is dissolved in 10 ml ofalcohol and stirred with 70 mg of FeCL₃ at room temperature. After theaddition of 100 ml of ethyl acetate, the mixture is washed twice with 50ml of a saturated EDTA solution (pH=7, adjusted with NaOH) and twicewith 50 ml of water. After drying the organic phase over sodium sulfate,contraction is carried out in vacuo to a solid residue.

Process 3

1 mmol of macrodiolide of the elaiophyline type is stirred in 100 ml ofisopropanol at room temperature for 24 hours with 250 mg of NaBH₄. Theexcess of reductant is decomposed by addition of acetone. The solvent isremoved by distillation in vacuo and the residue is taken up in ethylacetate. After extracting by shaking with water, the organic phase isdried over sodium sulfate and removed by distillation in vacuo.Chromatography on 100 g of silica gel, having a linear gradient of ethylacetate:hexane/1:5 in ethyl acetate (with compounds having R₁ =R₁ ' andR₂, R₃ ≠H) or chloroform:methanol/40:1 in chloroform/methanol/1:1 (withcompounds having R₁ =R₁ ' and R₂, R₃ =H) yields the reduced compounds.

Process 4

1 mmol of the compound from Example 22 (see Table 1) is suspended in 20ml of methylene chloride and stirred for 20 hours at 25° C. undernitrogen with 6 mmol of SEM chloride or MEM chloride and 2 ml (12 mmol)of diisopropylethylamine. After the addition of 5 ml of methanol, thesolvent is removed by distillation in vacuo. The residue is taken up inmethylene chloride and extracted by shaking with water. After dryingover sodium sulfate, the solvent is stripped off in vacuo.Chromatography on silica gel (100 g) having a linear gradient of ethylacetate:hexane/1:5 in ethyl acetate (about 5 liters) yields thecorresponding compounds.

Process 5

1 mmol of macrodiolide of the elaiophyline type is dissolved in 10 ml ofdichloromethane and 10 ml of pyridine. After addition of an excess ofcarboxylic acid anhydride and 1 mmol of 4-dimethylaminopyridine, themixture is stirred at room temperature until the reaction is completeaccording to the thin layer chromatogram (about 2 to 6 hours). Excessanhydride is decomposed by the addition of 5 ml of methanol with icecooling. The mixture is diluted with 50 ml of ethyl acetate, firstextracted three times each time using 20 ml of saturated sodium hydrogencarbonate solution, then using just so much 0.1 N HCl solution that theaqueous phase does not exceed pH 5, and finally one more time using 20ml of saturated sodium hydrogen carbonate solution. After drying theorganic phase over sodium sulfate and concentrating in vacuo, theproduct is either isolated by crystallization or by chromatography onsilica gel.

Process 6

1 mmol of macrodiolide of the elaiophyline type is stirred with anexcess of the relevant aldehyde or ketone, which in turn can be used asthe solvent, at room temperature, if appropriate diluting with aco-solvent such as dichloromethane, chloroform or tetrahydrofuran, inthe presence of catalytic amounts of an anhydrous Lewis acid such as iZnCL₂ ZnI₂, FeCL₃, CuCL₂ or CuSO₄, until the reaction is completeaccording to the thin layer chromatogram. After diluting with 50 ml ofethyl acetate and washing three times each time with 20 ml each of asaturated sodium hydrogen carbonate solution, the product is isolated bycolumn chromatography on silica gel.

Process 7

1 mmol of macrodiolide of the elaiophyline type is dissolved in asuitable solvent or solvent mixture and 10% by weight of hydrogenationcatalyst, preferably 10% of palladium on animal charcoal, are added. Areliable solvent system consists of a mixture of isopropanol/ethylacetate/water in the volume ratio 4/3/2. The hydrogenation takes placeat room temperature with magnetic stirring or shaking in a closedhydrogenation apparatus while maintaining a slight excess hydrogenpressure of up to 0.2 bar. Under these conditions, the reaction iscompleted in the course of 0.5 to 2 hours with the absorption of 4 mmolof H₂. After filtering off the catalyst and concentrating, the productmust still be purified in some cases by recrystallization or columnchromatography.

Process 8

1 mmol of macrodiolide of the elaiophyline type is dissolved in 10 to100 ml of anhydrous methanol and up to 40% by weight of driedhydrogenation catalyst, preferably 10% palladium on animal charcoal, areadded. The hydrogenation and product isolation takes place exactly asdescribed for process 7.

The compounds synthesized according to the previously describedprocesses 1 to 8 are shown in the following tables. The substituents inthe radical R^(1') are designated by R^(2'), R^(3'), R^(4'), R^(5') andR^(7'). In Table 1, the various substituents of the elaiophylinederivatives are given for the purpose of identifying the compounds. InTable 2, the particular preparation process, the individual processparameters, the type of reagent, the relative concentration of thereagent (with reference to the starting compound of the elaiophylinetype), the yield and also selected, characteristic analytical data forthe compounds obtained are given. An explanation of the expressions usedin the tables can be found at the end.

                                      TABLE 1                                     __________________________________________________________________________    Compound                                                                            Precursor                                                                           Hydr.                                                                             R.sup.1                                                                         R.sup.2                                                                              R.sup.3                                                                              R.sup.4                                                                         R.sup.5                                                                          R.sup.7                                                                         R.sup.1'                                                                        R.sup.2'                                                                             R.sup.3'                                                                             R.sup.4'                                                                        R.sup.5'                                                                          R.sup.7'         __________________________________________________________________________     1    Ela   -   II                                                                              Ac     Ac     H H  --                                                                              II                                                                              Ac     Ac     H H   --                2    Ela   -   II                                                                              Ac     Ac     H H  --                                                                              II                                                                              H      Ac     H H   --                3    Ela   -   II                                                                              H      Ac     H H  --                                                                              II                                                                              H      Ac     H H   --                4    Ela   -   II                                                                              H      Ac     H H  --                                                                              II                                                                              H      H      H H   --                5    Ela   -   II                                                                              p-BrBz p-BrBz H H  --                                                                              II                                                                              p-BrBz p-BrBz H H   --                6    Ela   -   II                                                                              p-BrBz p-BrBz H H  --                                                                              II                                                                              H      p-BrBz H H   --                7    Ela   -   II                                                                              H      p-BrBz H H  --                                                                              II                                                                              H      p-BrBz H H   --                8    Ela   -   II                                                                              H      p-BrBz H H  --                                                                              II                                                                              H      H      H H   --                9    Ela   -   II                                                                              Val    Val    H H  --                                                                              II                                                                              Val    Val    H H   --               10    1     -   II                                                                              Ac     Ac     H CH.sub.3                                                                         --                                                                              II                                                                              Ac     Ac     H CH.sub.3                                                                          --               11    1     -   II                                                                              Ac     Ac     H C.sub.2 H.sub.5                                                                  --                                                                              II                                                                              Ac     Ac     H C.sub.2 H.sub.5                                                                   --               12    2     -   II                                                                              Ac     Ac     H CH.sub.3                                                                         --                                                                              II                                                                              H      Ac     H CH.sub.3                                                                          --               13    Ela   -   II                                                                              2-C.sub.5 H.sub.3 O.sub.2                                                            2-C.sub.5 H.sub.3 O.sub.2                                                            H H  --                                                                              II                                                                              2-C.sub.5 H.sub.3 O.sub.2                                                            2-C.sub.5 H.sub.3                                                                    H.sub.2                                                                         H   --               14    13    -   II                                                                              2-C.sub.5 H.sub.3 O.sub.2                                                            2-C.sub.5 H.sub.3 O.sub.2                                                            H CH.sub.3                                                                         --                                                                              II                                                                              2-C.sub.5 H.sub.3 O.sub.2                                                            2-C.sub.5 H.sub.3                                                                    H.sub.2                                                                         CH.sub.3                                                                          --               15    Ela   -   II                                                                               ##STR20##    H H  --                                                                              II                                                                               ##STR21##    H H   --               16    Ela   -   II                                                                               ##STR22##    H H  --                                                                              II                                                                              C(O)Im C(O)Im H H   --               17    1     -   II                                                                              Ac     Ac     H H  --                                                                              III                                                                             Ac     Acn    H --  H                18    1     -   III                                                                             Ac     Ac     H -- H III                                                                             Ac     Ac     H --  H                19    9     -   II                                                                              Val    Val    H H  --                                                                              III                                                                             Val    Val    H --  H                20    9     -   III                                                                             Val    Val    H -- H III                                                                             Val    Val    H --  H                21    17    -   II                                                                              Ac     Ac     H CH.sub.3                                                                         --                                                                              III                                                                             Ac     Ac     H --  H                22    Ela   -   II                                                                              H      H      H CH.sub.3                                                                         --                                                                              II                                                                              H      H      H CH.sub.3                                                                          --               23    22    -   II                                                                              SEM    SEM    H CH.sub.3                                                                         --                                                                              II                                                                              SEM    SEM    H CH.sub.3                                                                          --               __________________________________________________________________________    Compound                                                                            Precursor                                                                           Hydr.                                                                             R.sup.1                                                                         R.sup.2                                                                              R.sup.3                                                                              R.sup.4                                                                         R.sup.5                                                                          R.sup.7                                                                         R.sup.1'                                                                        R.sup.2                                                                              R.sup.3                                                                              R.sup.4                                                                         R.sup.5                                                                           R.sup.7          __________________________________________________________________________    24    22    -   II                                                                              MEM    MEM    H CH.sub.3                                                                         --                                                                              II                                                                              MEM    MEM    H CH.sub.3                                                                          --               .sup. 25.sup.(t)                                                                    Ela   -   II                                                                              Ac     Ac     Ac                                                                              Ac --                                                                              II                                                                              Ac     Ac     Ac                                                                              Ac  --               26    Ela   -   II                                                                              Mes    Mes    H H  --                                                                              II                                                                              Mes    Mes    H H   --               27    Ela   -   II                                                                               ##STR23##    H H  --                                                                              II                                                                               ##STR24##    H H   --               28    27    -   II                                                                               ##STR25##    H CH.sub.3                                                                         --                                                                              II                                                                               ##STR26##    H CH.sub.3                                                                          --               29    Ela   -   II                                                                              Bz     Bz     H H  --                                                                              II                                                                              Bz     Bz     H H   --               30    29    -   II                                                                              Bz     Bz     H CH.sub.3                                                                         --                                                                              II                                                                              Bz     Bz     H CH.sub.3                                                                          --               31    Ela   +   II                                                                              H      H      H H  --                                                                              II                                                                              H      H      H H   --               32    1     +   II                                                                              Ac     Ac     H H  --                                                                              II                                                                              Ac     Ac     H H   --               33    2     +   II                                                                              Ac     Ac     H H  --                                                                              II                                                                              H      Ac     H H   --               34    3     +   II                                                                              H      Ac     H H  --                                                                              II                                                                              H      Ac     H H   --               35    4     +   II                                                                              H      Ac     H H  --                                                                              II                                                                              H      H      H H   --               36    5     +   II                                                                              p-BrBz p-BrBz H H  --                                                                              II                                                                              p-BrBz p-BrBz H H   --               37    6     +   II                                                                              p-BrBz p-BrBz H H  --                                                                              II                                                                              H      p-BrBz H H   --               38    7     +   II                                                                              H      p-BrBz H H  --                                                                              II                                                                              H      p-BrBz H H   --               39    8     +   II                                                                              H      p-BrBz H H  --                                                                              II                                                                              H      H      H H   --               40    31    +   II                                                                              Val    Val    H H  --                                                                              II                                                                              Val    Val    H H   --               41    53    +   II                                                                              Ac     Ac     H CH.sub.3                                                                         --                                                                              II                                                                              Ac     Ac     H CH.sub.3                                                                          --               42    32    +   II                                                                              Ac     Ac     H C.sub.2 H.sub.5                                                                  --                                                                              II                                                                              Ac     Ac     H C.sub.2 H.sub.5                                                                   --               43    33    +   II                                                                              Ac     Ac     H CH.sub.3                                                                         --                                                                              II                                                                              H      Ac     H CH.sub.3             44    31    +   II                                                                              2-C.sub.5 H.sub.3 OS                                                                 2-C.sub.5 H.sub.3 OS                                                                 H H  --                                                                              II                                                                              2-C.sub.5 H.sub.3 OS                                                                 2-C.sub.5 H.sub.3                                                                    HS                                                                              H   --               45    44    +   II                                                                              2-C.sub.5 H.sub.2 OS                                                                 2-C.sub.5 H.sub.3 OS                                                                 H CH.sub.3                                                                         --                                                                              II                                                                              2-C.sub.5 H.sub.3 OS                                                                 2-C.sub.5 H.sub.3                                                                    HS                                                                              CH.sub.3                                                                          --               46    31    +   II                                                                               ##STR27##    H H  --                                                                              II                                                                               ##STR28##    H H   --               47    31    +   II                                                                               ##STR29##    H H  --                                                                              II                                                                              C(O)Im C(O)Im H H   --               48    32    +   II                                                                              Ac     Ac     H H  --                                                                              III                                                                             Ac     Ac     H --  H                49    32    +   III                                                                             Ac     Ac     H -- H III                                                                             Ac     Ac     H --  H                50    40    +   II                                                                              Val    Val    H H  --                                                                              III                                                                             Val    Val    H --  H                51    40    +   III                                                                             Val    Val    H -- H III                                                                             Val    Val    H --  H                52    48    +   II                                                                              Ac     Ac     H CH.sub.3                                                                         --                                                                              III                                                                             Ac     Ac     H --  H                53    Ela   +   II                                                                              H      H      H CH.sub.3                                                                         --                                                                              II                                                                              H      H      H CH.sub.3                                                                          --               54    31    +   II                                                                              SEM    SEM    H H  --                                                                              II                                                                              SEM    SEM    H H   --               55    31    +   II                                                                              MEM    MEM    H H  --                                                                              II                                                                              MEM    MEM    H H   --               56    25    +   II                                                                              Ac     Ac     Ac                                                                              Ac --                                                                              II                                                                              Ac     Ac     Ac                                                                              Ac  --               57    31    +   II                                                                              Bz     Bz     H H  --                                                                              II                                                                              Bz     Bz     H H   --               58    57    +   II                                                                              Bz     Bz     H CH.sub.3                                                                         --                                                                              II                                                                              Bz     Bz     H CH.sub.3                                                                          --               __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________               Reaction                                                                            Reaction     Equivalents                                                                         Yield                                     Compound                                                                            Process                                                                            time (h)                                                                            temp. (°)                                                                   Reagent of reagent                                                                          (%)                                       __________________________________________________________________________     1    1    24    20   Ac.sub.2 O                                                                            10    97                                         2    1    12    -20  Ac.sub.2 O                                                                            5     62                                         3    1    14    -20  Ac.sub.2 O                                                                            2.5   66                                         4    1    8     -20  Ac.sub.2 O                                                                            1.5   46                                         5    1    10    20   p-BrBzCl                                                                              5     64                                         6    1    3     20   p-BrBzCl                                                                              3.3   33                                         7    1    3     -5   p-BrBzCl                                                                              2.6   54                                         8    1    5     -35  p-BrBzCl                                                                              1.5   32                                         9    1    90    20   Val.sub.2 O                                                                           8     74                                        10    2    0.5   20   CH.sub.3 OH                                                                           Solv. 82                                        11    2    1     20   C.sub.2 H.sub.5 OH                                                                    Solv. 79                                        12    2    0.5   20   CH.sub.3 OH                                                                           Solv. 81                                        13    5    6     20   (2-C.sub.5 H.sub.3 O.sub.2).sub.2 O                                                   12    83                                        14    2    0.5   20   CH.sub.3 OH                                                                           Solv. 90                                        15    1    72    20   Im.sub.2 CO                                                                           5     37                                        16    1    72    20   Im.sub.2 CO                                                                           5     35                                        17    3    12    20   NaBH.sub.4                                                                            6.5   33                                        18    3    12    20   NaBH.sub.4                                                                            6.5   42                                        19    3    12    20   NaBH.sub.4                                                                            6.5   30                                        20    3    12    20   NaBH.sub.4                                                                            6.5   50                                        21    2    0.5   20   CH.sub.3 OH                                                                           Solv. 80                                        22    2    0.5   20   CH.sub.3 OH                                                                           Solv. 95                                        23    4    24    20   SEMCl   8     35                                        24    4    24    20   MEMCl   8     30                                        .sup. 25.sup.(t)                                                                    5    12    20   Ac.sub.2 O                                                                            40    70                                        26    1    1     20   MesCl   5     41                                        27    6    14    30   AcCH.sub.3                                                                            100   20                                        28    2    0.5   20   CH.sub.3 OH                                                                           Solv. 90                                        29    5    6     20   Bz.sub.2 O                                                                            12    86                                        30    2    0.5   20   CH.sub.3 OH                                                                           Solv. 79                                        31    7    2     20   H.sub.2 /Pd                                                                           4     89                                        32    7    1.5   20   H.sub.2 /Pd                                                                           4     90                                        33    7    1.5   20   H.sub.2 /Pd                                                                           4     75                                        34    7    2     20   H.sub.2 /Pd                                                                           4     70                                        35    7    2     20   H.sub.2 /Pd                                                                           4     86                                        36    7    3     20   H.sub.2 /Pd                                                                           4     71                                        37    7    2.5   20   H.sub.2 /Pd                                                                           4     79                                        38    7    3     20   H.sub.2 /Pd                                                                           4     86                                        39    7    3     20   H.sub.2 /Pd                                                                           4     80                                        40    1    72    20   Val.sub.2 O                                                                           8     77                                        41    1    18    20   Ac.sub.2 O                                                                            20    82                                        42    2    1     20   C.sub.2 H.sub.5 OH                                                                    Solv. 89                                        43    2    0.5   20   CH.sub.3 OH                                                                           Solv. 84                                        44    5    8     20   (2-C.sub.5 H.sub.3 OS).sub.2 O                                                        12    79                                        45    2    0.5   20   CH.sub.3 OH                                                                           Solv. 90                                        46    1    72    20   Im.sub.2 CO                                                                           5     39                                        47    1    72    20   Im.sub.2 CO                                                                           5     31                                        48    3    12    20   NaBH.sub.4                                                                            6.5   28                                        49    3    12    20   NaBH.sub.4                                                                            6.5   44                                        50    3    12    20   NaBH.sub.4                                                                            6.5   39                                        51    3    12    20   NaBH.sub.4                                                                            6.5   54                                        52    2    0.5   20   CH.sub.3 OH                                                                           Solv. 85                                        53    8    22    20   H.sub.2 /Pd                                                                           4     87                                        54    4    24    20   SEMCl   8     32                                        55    4    24    20   MEMCl   8     38                                        .sup. 56.sup.(t)                                                                    8    2     20   H.sub.2 /Pd                                                                           4     77                                        57    5    6     20   Bz.sub.2 O                                                                            20    73                                        58    2    0.5   20   CH.sub.3 OH                                                                           Solv. 83                                        __________________________________________________________________________            Selected analytical data.sup.(tt)                                                20            Elemental analysis                                           M.p.                                                                             [α.sub.D ]                                                                       FAB-MS                                                                             C   C   H   H                                        Compound                                                                              (°C.)                                                                     (C = 1, CH.sub.3 OH)                                                                   MNa.sup.+                                                                          (calc.)                                                                           (found)                                                                           (calc.)                                                                           (found)                                  __________________________________________________________________________     1      186         1215                                                       2                  1173                                                       3                  1131                                                       4                  1089                                                       5      194                                                                    6      182                                                                    7      205                                                                    8      160                                                                    9      173                                                                   10                  1243                                                      11                  1271                                                      12                  1201                                                      13                  1423                                                      14                  1451                                                      15      207                                                                               +3°                                                        16      160                                                                              -42°                                                        17                  1217                                                      18                  1219                                                      19                  1385                                                      20                  1387                                                      21                  1231                                                      22                  1075                                                      23                  1595                                                      24                  1427                                                      .sup. 25.sup.(t)                                                                         +10°   61.75                                                                             61.55                                                                             7.69                                                                              7.65                                     26                  1359                                                      27                  1127                                                      28                  1155                                                      29         -96°                                                        30                       68.64                                                                             68.72                                                                             7.40                                                                              7.60                                     31      198                                                                              -77°                                                        32      125                                                                              -86°                                                        33                  1181                                                      34                  1139                                                      35                  1097                                                      36                       55.79                                                                             56.95                                                                             6.16                                                                              6.27                                     37                       56.93                                                                             56.72                                                                             6.69                                                                              6.89                                     38                       58.37                                                                             58.12                                                                             7.35                                                                              7.50                                     39                       60.23                                                                             60.04                                                                             8.20                                                                              8.44                                     40                  1391                                                      41         -53°                                                        42                  1279                                                      43                  1209                                                      44                       60.30                                                                             59.99                                                                             7.11                                                                              6.89                                     45                       60.77                                                                             60.57                                                                             7.25                                                                              7.39                                     46                       61.97                                                                             62.20                                                                             8.54                                                                              8.33                                     47                       60.65                                                                             61.00                                                                             7.92                                                                              7.69                                     48                  1225                                                      49                  1227                                                      50                  1393                                                      51                  1395                                                      52                  1239                                                      53      114                                                                                -49.5                                                            54                  1603                                                      55                  1435                                                      .sup. 56.sup.(t)         61.38                                                                             61.30                                                                             8.24                                                                              8.30                                     57      190                                                                              -106                                                               58                       68.27                                                                             67.97                                                                             7.91                                                                              7.99                                     __________________________________________________________________________

The compounds in general melt with decomposition. All remainingsubstances are amorphous solids. The structure assignment is based inparticular on ¹ H, ¹³ C, 2D-DNMR, FAB-MS and IR spectroscopy.

    ______________________________________                                        Key to the table                                                              ______________________________________                                        Ela:      elaiophyline R.sup.1,R.sup.1' = II and R.sup.2,R.sup.3,R.sup.4,R              .sup.5 = H                                                          Ac:       --CO--CH.sub.3                                                      p-Br--Bz: para-bromobenzoyl                                                   Val:      --Co--(CH.sub.2).sub.3 CH.sub.3                                     Solv.:    reagent = solvent                                                   2-C.sub.5 H.sub.3 O.sub.2 :                                                             2-furoyl                                                            Im.sub.2 CO:                                                                            carbonyldiimidazole                                                 Im:       1-imidazolyl                                                        SEM:      (CH.sub.3).sub.3 SiCH.sub.2 CH.sub.2 OCH.sub.2 --                   MEM:      CH.sub.3 OCH.sub.2 CH.sub.2 OCH.sub.2 --                            Mes:      --SO.sub.2 CH.sub.3                                                 Bz:       benzoyl                                                             2-C.sub.5 H.sub.3 OS:                                                                   2-thienoyl                                                          Hydr.:    in this column is given whether the macro-                                    diolide ring is hydrogenated (+) or not (-)                         II or III:                                                                              in the columns under R.sup.1 and R.sup.1' is given which                      formula type (see formula I) the substituents                                 R.sup.1 and R.sup.1' belong to.                                     ______________________________________                                    

Anthelmintic action of the elaiophyline derivatives

The anthelmintic action of the elaiophyline derivatives was investigatedin lambs having a body weight of 30 to 40 kg. for this, the lambs wereartificially infected with infective stages of abomasum nematodes(Haemunchus cortortus). After the end of the development time(prepatency period) of the nematodes, the administration of theelaiophyline derivatives took place.

By coproscopic investigations before and up to 14 days after theadministration of the elaiophyline derivatives and subsequent sectionwith helminthological working up, the percentage reduction of the sheepnematodes was ascertained (see Table 3). Elaiophyline was used as thecomparison substance. Additionally, the antibacterial activity of theelaiophyline derivatives according to the invention against Staph.aureus and Strept. pyogenes was also ascertained. Surprisingly, thecompounds according to the invention show no or only very lowantibacterial activity. Precisely for this reason, the compoundsaccording to the invention are in particular suitable for use asanthelmintics, since here an antibacterial action is undesired.

                                      TABLE 3                                     __________________________________________________________________________    Administered  Reduction of                                                                           Antibacterial activity                                 compound from                                                                          Dose H. contortus                                                                           (μg/ml) against                                     Example  (mg/kg)                                                                            (%)      Staph. aureus.                                                                       Strept. pyogenes                                __________________________________________________________________________    Elaiophyline                                                                           2.5 (s.c.)                                                                         35-45     1.56  1.56                                                     5.0 (oral)                                                                         70-95                                                            1       2.5 (s.c.)                                                                         70-90    >100   >100                                                     5.0 (oral)                                                                         40-60                                                            2       2.5 (s.c.)                                                                         50-70    >100   6.25                                                     5.0 (oral)                                                                         30-40                                                            5       2.5 (s.c.)                                                                          5-10    >100   >100                                                     5.0 (oral)                                                                          5-10                                                            8       2.5 (s.c.)                                                                         50-70    >100   3.13                                                     5.0 (oral)                                                                         10-20                                                            9       2.5 (s.c.)                                                                         50-70    50.0   50.0                                                     5.0 (oral)                                                                         50-70                                                           10       2.5 (s.c.)                                                                         10-20    >100   >100                                                     5.0 (oral)                                                                         30-50                                                           15       2.5 (s.c.)                                                                          5-10    >100   >100                                                     5.0 (oral)                                                                          5-10                                                           16       2.5 (s.c.)                                                                          5-10    >100   >100                                                     5.0 (oral)                                                                         --                                                              17       2.5 (s.c.)                                                                         30-50    25.0   25.0                                                     5.0 (oral)                                                                         30-50                                                           22       2.5 (s.c.)                                                                         30-40     3.13  1.56                                                     5.0 (oral)                                                                         60-75                                                           29       2.5 (s.c.)                                                                         10-20    >100   >100                                                     5.0 (oral)                                                                         60-80                                                           31       2.5 (s.c.)                                                                         30-40    >100   >100                                                     5.0 (oral)                                                                         50-75                                                           32       2.5 (s.c.)                                                                         50-60    >100   >100                                                     5.0 (oral)                                                                         40-60                                                           41       2.5 (s.c.)                                                                         40-60    >100   >100                                                     2.5 (oral)                                                                         60-80                                                           53       2.5 (s.c.)                                                                         40-50      25   6.25                                                     3.8 (oral)                                                                         60-75                                                           57       2.5 (s.c.)                                                                         20-30    >100   >100                                                     5.0 (oral)                                                                         40-60                                                           __________________________________________________________________________

We claim:
 1. An elaiophyline derivative of the formula I ##STR30## wherethe C-13 C double bonds in the macrodielide ring of the compound of theformula I can also be hydrogenated and in whichR¹ is a radical of theformula II or III ##STR31## in which R² and r³ are identical ordifferent and denote hydrogen or a radical of the formula IV or IV'##STR32## in which n denotes 1 to 3 and R⁶ denotes C₁ -C₁₅ -alkyl, C₂-C₁₅ -alkenyl, C₂ -C₁₅ -alkynyl, C₃ -C₉ -cycloalkyl, a radical selectedfrom the group consisting of phenyl, naphthyl, thiophene, furan,pyridine, pyrimidine and pyrazine, where said radical can be substitutedby halogen, nitro, cyano, hydroxyl, C₁ -C₄ -alkyl or C₁ -C₄ -alkoxy andwhere for the case in which R³ is hydrogen, R² is also hydrogen,or inwhich R² and R³ are identical and denote C₁ -C₄ -alkyl, benzyl, allyl,methoxyethoxymethyl, methoxymethyl, β-trimethylsilylethoxymethyl,trimethylsilyl, triethylsilyl, dimethylphenylsilyl,dimethylcyclohexylsilyl or dimethyl tertiary butylsilylor R² and R³denote sulfonates of the formula SO₂ Rin which R¹⁰ denotes C₁ -C₁₀-aklyl, phenyl or p-tolylor R² and R³ represent a radical of the formulaV or V' ##STR33## in which n denotes 1 to 3 X denotes oxygen or sulfurR¹² denotes C₁ -C₁₅ -alkyl, C₃ -C₉ -cycloalkyl, phenyl, naphthyl,pyridyl, pyrimidyl or pyrazinyl, where the phenyl, napthyl, pyridyl,pyrimidyl or pyrazinyl radicals can be substituted by halogen, nitro,cyano or C₁ -C₄ -alkoxy and Z denotes oxygen, --N--H or a radical--N--R¹² or --N--(CH₂)_(n) -- R¹², where n and R¹² have theabove-mentioned meaningsor in which R² and R³ together represent aradical of the formula VI ##STR34## in which R⁸ and R⁹ are identical ordifferent and denote hydrogen or unbranched C₁ -C₁₀ -alkyl or where R⁸and R⁹ represent an alkylene chain, which together with the carbon atomcarrying it, forms a 5-, 6- or 7-membered ringor in which R² and R³, forthe case in which R¹ is a radical of the formula II, are identical andrepresent a radical of the formula VIII ##STR35## in which X denotesoxygen or sulfuror R² and R³, for the case in which R¹ is a radical ofthe formula II, together represent a radical of the formula ##STR36##wherein X denotes oxygen or sulfurand in which R⁴, provided that R² andR³ are hydrogen, denotes hydrogen or, for the case in which R² and R³ donot denote hydrogen, is hydrogen or a radical of the formula IV or IV'##STR37## n and R⁶ have the above-mentioned meanings and R⁵ is hydrogenor a radical of the formula --(CH₂)_(n) --R⁶ where n and R⁶ have theabove-mentioned meaningsand in which R⁷ denotes hydrogen or--providedthat R², R³ and R⁴ do not simultaneously denote hydrogen--forms aradical of the formula IV or IV'--as defined above--and in which R^(1')has the same meaning as R¹, where the two radicals R¹ and R^(1') can besubstituted both by identical--except for the radicals R⁴ and R⁵ and forthe case in which R² and R³ together form a radical of the formulaVI--and different substituents, with the exception that when R¹ is aradical of the formula II in which R² and R³ form a radical of theformula VIII or in which R² and R³ together form a radical of theformula >C=X, for R^(1') the radicals R² and R³ in the radical of theformula II or III are not simultaneously hydrogen,excluding elaiophylineitself, elaiophyline having a hydrogenated macrodiolide ring, and alsocompounds of the formula I, wherein the macrodiolide ring ishydrogenated or unhydrogenated and in which R¹ and R^(1') are identicalor different and represent a radical of the formula II or III, whereinR² and R³ denote hydrogen or acetyl and R⁴ and R⁵ or R⁷ denote hydrogenand likewise also excluding the compounds of the formula I in which themacrodiolide ring is unhydrogenated and wherein R¹ and R^(1')simultaneously represent a radical of the formula II, wherein R², R³ andR⁴ denote hydrogen and wherein R⁵ denotes a radical of the formula--(CH₂)_(n) --R⁶ where n and R⁶ have the above-mentioned meanings. 2.The elaiophyline derivative of the formula I as claimed in claim 1,where the C--C double bonds in the macrodiolide ring of the compound ofthe formula I can also be hydrogenated and in which R¹ is a radical ofthe formula II or III, as given in claim 1, in whichR² and R³ areidentical or different and denote hydrogen or a radical of the formulaIV or IV, as given in claim 1,in which n denotes 1 to 3 and R⁶ denotesC₁ -C₅ -alkyl, C₂ -C₅ -alkenyl, C₂ -C₆ -alkynyl, C₃ -C₆ -cycloalkyl,phenyl or furyl or thienyl, where the phenyl, furyl and thienyl radicalscan be substituted by halogen, nitro, cyano, hydroxyl, C₁ -C₄ -alkyl orC₁ -C₄ -alkoxy and where, for the case in which R³ is hydrogen, R² isalso hydrogen,or in which R² and R³ are identical and denotemethoxyethoxymethyl, methoxymethyl, β-trimethylsilylethoxymethyl,trimethylsilyl, triethylsilyl, dimethylphenylsilyl,dimethycyclohexylsilyl or dimethyl tertriary butylsilylor R² and R³denote sulfonates of the formula SO₂ R¹⁰,in which R¹⁰ denotes C₁ -RC₄-alkyl, phenyl or p-tolylor R² and R³ represent a radical of the formulaV or V', as given in claim 1,in which n denotes 1, X denotes oxygen, R¹²denotes C₁ -C₄ -alkyl, C₃ -C₆ -cycloalkyl, phenyl or naphthyl, where thephenyl or napthyl radical can be substituted by halogen, nitro, cyano orC₁ -C₄ -alkoxy and Z denotes oxygen or --N--Hor in which R² and R³together represent a radical of the formula VI as given in claim 1, inwhich R⁸ and R⁹ are identical or different and denote hydrogen orunbranched C₁ -C₄ -alkyl or where R⁸ and R⁹ represent an alkylene chainwhich, together with carbon atom carrying it forms a 5- or 6-memberedringor in which R² and R³, for the case in which R¹ is a radical of theformula II, as given in claim 1, are identical and represent a radicalof the formula VIII, as given in claim 1,in which X denotes oxygenor R²and R³, for the case in which R¹ is a radical of the formula II, asgiven in claim 1, together represent a radical of the formula >C=X,inwhich X denotes oxygenand in which R⁴, provided R² and R³ are hydrogen,denotes hydrogen or, for the case in which R² and R³ do not denotehydrogen, is hydrogen or a radical of the formula IV or IV', as given inclaim 1,in which n is 1 to 3 and R⁶ has the above-mentioned meanings,and R⁵ is hydrogen or a radial of the formula --(CH₂)_(N) --R⁶ where nis 1 to 3 and R⁶ has the meanings as given above, and in which R⁷denotes hydrogen or --provided R², R³ and R⁴ do not simultaneouslydenote hydrogen--forms a radical of the formula IV or IV' as given inclaim 1 and defined above and in which R^(1') has the same meaning asR¹, in which the two radicals R¹ and R^(1') can be substituted both byidentical substituents and also--except for the radicals R⁴ and R⁵ andfor the case in which R² and R³ together form a radical of the formulaVI--different substituents, with the exception that when R¹ is a radicalof the formula II as given in claim 1 in which R² and R³ form a radicalof the formula VIII as given in the claim 1, or in which R² and R³together form a radical of the formula >C=X, for R^(1') the radicals R²and R³ in the radical of the formula II or III as given in claim 1, arenot simultaneously hydrogen,excluding elaiophyline itself, elaiophylinehaving a hydrogenated macrodiolide ring, and also compounds of theformula I, in which the macrodiolide ring is hydrogenated orunhydrogenated and in which R¹ and R^(1') are identical or different andrepresent a radical of the formula II or III, in which R² and R³ denotehydrogen or acetyl and R⁴ and R⁵ or R⁷ denote hydrogen and likewise alsoexcluding the compounds of the formula I, in which the macrodiolide ringis unhydrogenated and in which R¹ and R^(1') simultaneously represent aradical of the formula II, in which R², R³ and R⁴ denote hydrogen and inwhich R⁵ denotes a radical of the formula --(CH₂)_(n) --R⁶ where n andR⁶ have the above-mentioned meanings.
 3. An elaiophyline derivative ofthe formula I as claimed in claim 1, where the C--C double bonds in themacrodiolide ring of the compound of the formula I can also behydrogenated and in which R¹ is a radical of the formula II or III--asgiven in claim 1, in whichR² and R³ are identical or different anddenote hydrogen or a radical of the formula IV or IV', as given in claim1 in which n denotes 1, R⁶ denotes C₁ -C₅ -alkyl, cyclohexyl, phenyl,furyl or thienyl, in which the phenyl furyl, and thienyl radicals can besubstituted with fluorine, chlorine or bromine and where, for the casein which R³ is hydrogen, R² is also hydrogen,or in which R² and R³ areidentical and denote methoxyethoxymethyl, methoxymethyl,β-trimethylsilylethoxymethyl, trimethylsilyl, triethylsilyl,dimethylphenylsilyl, dimethycyclohexylsilyl or dimethyl tertiarybutylsilylor R² and R³ denote sulfonates of the formula SO₂ R¹⁰ in whichR¹⁰ denotes methyl, phenyl or p-tolylor R² and R³ represent a radical ofthe formula V or V', as given in claim 1, in which n denotes 1 x denotesoxygen R¹² denotes cyclohexyl, or phenyl or napthyl, where the phenyl ornapthyl radical is optionally substituted by halogen, nitro, cyano or C₁-c₄ -alkoxy and Z denotes oxygen or --N--H,or in which R² and R³together represent a radical of the formula VI, as given in claim 1,inwhich R⁸ and R⁹ are identical or different and denote hydrogen orunbranched C₁ -C₄ -alkyl or where R⁸ and R⁹ represent an alkylene chainwhich, together with the carbon atom carrying it forms a 5- or6-membered ringor in which R² and R³, for the case in which R¹ is aradical of the formula II, as given in claim 1, are identical andrepresent a radical of the formula VIII, as given in claim 1,in which Xdenotes oxygenor R² and R³, for the case in which R¹ is a radical of theformula II, as given in claim 1, together represent a radical of theformula C=X,in which X denotes oxygenand in which R⁴, provided R² and R³are hydrogen, denotes hydrogen or, for the case in which R² and R³ donot denote hydrogen, is hydrogen or a radical of the formula IV or IV',as given in claim 1,in which n is 1 and R⁶ has the meanings given aboveand R⁵ is hydrogen or a radical of the formula --(Ch₂)_(n) --R⁶ in whichn is 1 and R⁶ has the meanings given above and in which R⁷ denoteshydrogen or--provided R² R³ and R⁴ do not simultaneously denotehydrogen--forms a radical of the formula IV or IV'--as given in claim 1and defined above --and in which R^(1') has the same meaning as R¹,where the two radicals R¹ and R^(1') can be substituted both withidentical substituents and also --except for the radicals R⁴ and R⁵ andfor the case in which R² and R³ together form a radical of the formulaVI--different substituents, with the exception that when R¹ is a radicalof the formula II, as given in claim 1, in which R² and R³ form aradical of the formula VIII, as given in claim 1, or in which R² and R³together form a radical of the formula ##STR38## for R¹ the radicals R²and R³ in the radial of the formula II or III, as given in claim 1, arenote simultaneously hydrogen,excluding elaiophyline itself, elaiophylinehaving a hydrogenated macrodiolide ring, and also compounds of theformula I, in which the macrodiolide ring is hydrogenated orunhydrogenated and in which R¹ and R¹, are identical or different andrepresent a radical of the formula II or III, in which R² and R³ denotehydrogen or acetyl and R⁴ and R⁵ or R⁷ denote hydrogen and likewise alsoexcluding the compounds of the formula I in which the macrodiolide ringis not hydrogenated and in which R¹ and R¹ , simultaneously represent aradical of the formula II, in which R², R³ and R⁴ denote hydrogen and inwhich R⁵ denotes a radical of the formula --(CH₂)_(n) --R⁶ where n andR⁶ have the above-mentioned meanings.
 4. A pharmaceutical compositionfor use in the treatment of anthelmintic disorders comprising atherapeutically effective amount of at least one of the elaiophylinederivatives of the formula I as claimed in claim 1, wherein the C--Cdouble bonds in the macrodiolide ring of the compound of the formula (I)can also be hydrogenated and in whichR¹ is a radical of the formula IIor III, in which R² and R³ are identical or different and denotehydrogen, or a radical of the formula IV or IV' in which n denotes 1 to3 and R⁶ denotes C₁ -C₁₅ -alkenyl, C₂ -C₁₅ -alkynyl, C₃ -C₉ -cycloalkyl,aryl or heteroaryl radical selected from the group consisting of phenyl,naphthyl, thiophene, furan, pyridine, pyrimidine or pyrazine, whereinsaid aryl and heteroaryl radicals can be substituted by halogen, nitro,cyano, hydroxyl, C₁ -C₄ -alkyl or C_(1-C) ₄ -alkoxy and where for thecase inwhich R³ is hydrogen, R² is also hydrogen, or in which R² and R³are identical and denote C₁ -C₄ -alkyl, benzyl, allyl,methoxyethoxymethyl, methoxymethyl, β-trimethylsilylethoxymethyl,trimethylsilyl, triethylsilyl, dimethylphenylsilyl,dimethylcyclohexylsilyl or dimethyl tertiary butylsilylor R² and R³denote sulfonates of the formula SO₂ R¹⁰ in which R¹⁰ denotes C₁ -C₁₀-alkyl, phenyl or p-tolylor R² and R³ represent a radical of the formulaV or V'in which n denotes 1 to 3 X denotes oxygen or sulfur R¹² denotesC₁ -C₁₅ -alkyl, C₃ -C₉ -cycloalkyl, phenyl, napthyl, pyridyl, pyrimidylor pyrazinyl, where the phenyl, napthyl, pyridyl, pyrimidyl or pyrazinylradicals can be substituted by halogen, nitro, cyano or C₁ -C₄ -alkoxyand denotes oxygen, --N--H or a radical --N--R¹² or --N--(CH₂)-- R¹²,where n and R¹² have the above-mentioned meaningsor in which R² and R³together represent a radical of the formula VIin which R⁸ and R⁹ areidentical or different and denote hydrogen or unbranched C₁ -C₁₀ -alkylor where R⁸ and R⁹ represent an alkylene chain, which together with thecarbon atom carrying it, forms a 5-, 6- or 7-membered ringor in which R²and R³, for the case in which R¹ is a radical of the formula II, areidentical and represent a radical of the formula VIIIin which X denotesoxygen or sulfuror R² and R³, for the case in which R¹ is a radical ofthe formula II, together represent a radical of the formula

    ≧C=X,

wherein X denotes oxygen or sulfurand in which R⁴, provided that R² andR³ are hydrogen, denotes hydrogen or, for the case in which R² and R³ donot denote hydrogen, is hydrogen or a radical of the formula IV or IV' nand R⁶ have the above-mentioned meaningsand R⁵ is hydrogen or a radicalof the formula --(CH₂)_(n) --R⁶ where n and R⁶ have the above-mentionedmeaningsand in which R⁷ denotes hydrogen or--provided that R², R³ and R⁴do not simultaneously denote hydrogen--forms a radical of the formula IVor IV' as defined above--and in which R¹, has the same meaning as R¹,where the two radicals R¹ and R¹ ' can be substituted both byidentical-13 except for the radicals R⁴ and R⁵ and for the case in whichR² and R³ together form a radical of the formula VI--and differentsubstituents, with the exception that when R¹ is a radical of theformula II in which R² and R³ form a radical of the formula VIII or inwhich R² and R³ together form a radical of the formula >C=X, for R¹ 'the radicals R² and R³ in the radical of the formula II or III are notesimultaneously hydrogen,excluding elaiophyline, together with an inertcarrier.
 5. A pharmaceutical composition for use in the treatment ofanthelmintic disorders comprising a therapeutically effective amount ofat least one of the elaiophyline derivatives of the formula I, asclaimed in claim 2,wherein the C--C double bonds in the macrodiolidering of the compound of the formula I can also be hydrogenated and inwhich R¹ is a radical of the formula II or III, in which R² and R³ areidentical or different and denote hydrogen or a radical of the formulaIV or IV,in which n denotes 1 to 3 and R⁶ denotes C₁ -C₅ -alkyl, C₂ -C₅-alkenyl, C₂ -C₆ -alkynyl, C₃ -C₆ cycloalkyl, phenyl or furyl orthienyl, where the phenyl, furyl and thienyl radicals can be substitutedby halogen, nitro, cyano, hydroxyl, C₁ -C₄ -alkyl or C₁ -C₄ -alkoxy andwhere, for the case in which R³ is hydrogen, R² is also hydrogen,or inwhich R² and R³ are identical and denote methoxyethoxymethyl,methoxymethyl, β-trimethylsily ethoxymethyl, trimethylsilyl,triethylsilyl, dimethylphenylsilyl, dimethycyclohexylsilyl or dimethyltertiary butylsilylor R² and R³ denote sulfonates of the formula SO₂R¹⁰,in which R¹⁰ denotes C₁ -C₄ -alkyl, phenyl or p-tolylor R² and R³represent a radical of the formula V or V',in which n denotes 1, Xdenotes oxygen, R¹² denotes C₁ -C₄ -alkyl, C₃ -C₆ -cycloalkyl or phenyland naphthyl, where the phenyl and napthyl radical can be substituted byhalogen, nitro, cyano or C₂ -C₄ -alkoxy and Z denotes oxygen or --N--Horin which R² and R³ together represent a radical of the formula VI, inwhich R⁸ and R⁹ are identical or different and denote hydrogen orunbranched C₁ -C₄ -alkyl or where R⁸ and R⁹ represent an alkylene chainwhich, together with carbon atom carrying it forms a 5- or 6-memberedringor in which R² and R³, for the case in which R¹ is a radical of theformula II are identical and represent a radical of the formula VIII,inwhich X denotes oxygenor R² and R³, for the case in which R¹ is aradical of the formula II together represent a radical of the formula##STR39## in which X denotes oxygenand in which R⁴, provided R² and R³are hydrogen, denotes hydrogen or, for the case in which R² and R³ donot denote hydrogen, is hydrogen or a radical of the formula IV orIV',in which n is 1 to 3 and R⁶ has the meanings as given above,and R⁵is hydrogen or a radical of the formula--(CH₂)_(n) --R⁶ where n is 1 to3 and R⁶ has the meanings as given above,and in which R⁷ denoteshydrogen or--provided R², R³ and R⁴ do not simultaneously denotehydrogen--forms a radical of the formula IV or IV' and defined aboveandin which R^(1') has the same meaning as R¹, in which the two radicals R¹and R^(1') can be substituted both by identical substituents andalso--except for the radicals R⁴ and R⁵ and for the case in which R² andR³ together form a radical of the formula VI--different substituents,with the exception that when R¹ is a radical of the formula II in whichR² and R³ form a radical of the formula VIII, or in which R² and R³together form a radical of the formula C=X, for R^(1') the radicals R²and R³ in the radical of the formula II or III, are note simultaneouslyhydrogen,excluding elaiophyline, together with an inert carrier.
 6. Apharmaceutical composition for use in the treatment of anthelminticdisorders comprising a therapeutically effective amount of at least oneof the elaiophyline derivatives of the formula I, as claimed in claim3,wherein the C--C double bonds in the macrodiolide ring of the compoundof the formula I can also be hydrogenated and in which R¹ is a radicalof the formula II or III, in which R² and R³ are identical or differentand denote hydrogen or a radical of the formula IV or IV', in which ndenotes 1, R⁶ denotes C₁ -C₅ -alkyl, cyclohexyl, phenyl, furyl orthienyl, in which the phenyl, furyl, and thienyl radicals are which canbe substituted with fluorine, chlorine or bromine and where, for thecase in which R³ is hydrogen, R² is also hydrogen,or in which R² and R³are identical and denotes methoxyethoxymethyl, methoxymethyl,β-trimethylsilylethoxymethyl, trimethylsilyl, triethylsilyl,dimethylphenylsilyl, dimethycyclohexylsilyl or dimethyl tertiarybutylsilylor R² and R³ denote sulfonates of the formula SO₂ R¹⁰ in whichR¹⁰ denotes methyl, phenyl or p-tolylor R² and R³ represent a radical ofthe formula V or V', in which n denotes 1 x denotes oxygen R¹² denotescyclohexyl, or phenyl or napthyl, where the phenyl or napthyl radicalcan be substituted by halogen, nitro, cyano or C₁ -C₄ -alkoxy and Zdenotes oxygen or --N--H,or in which R² and R³ together represent aradical of the formula VI,in which R⁸ and R⁹ are identical or differentand denote hydrogen or unbranched C₁ -C₄ -alkyl or where R⁸ and R⁹represent an alkylene chain which, together with the carbon atomcarrying it forms a 5- or 6-membered ringor in which R² and R³, for thecase in which R¹ is a radical of the formula II, are identical andrepresent a radical of the formula VIII,in which X denotes oxygenor R²and R³ for the case in which R¹ is a radical of the formula II, togetherrepresent a radical of the formula C=X,in which X denotes oxygenand inwhich R⁴, provided R² and R³ are hydrogen, denotes hydrogen or, for thecase in which R² and R³ do not denote hydrogen, is hydrogen or a radicalof the formula IV or IV',in which n is 1 and R⁶ has the meanings givenaboveand R⁵ is hydrogen or a radical of the formula --(CH₂)_(n) --R⁶ inwhich n is 1 and R⁶ has the meanings given aboveand in which R⁷ denoteshydrogen or--provided R², R³ and R⁴ do not simultaneously denotehydrogen--forms a radical of the formula IV or IV'--and defined above--and in which R^(1') has the same meaning as R¹, where the two radicalsR¹ and R^(1') can be substituted both with identical substituents andalso --except for the radicals R⁴ and R⁵ and for the case in which R²and R³ together form a radical of the formula VI--differentsubstituents, with the exception that when R¹ is a radical of theformula II, in which R² and R³ form a radical of the formula VIII, or inwhich R² and R³ together form a radical of the formula ##STR40## for R¹the radicals R² and R³ in the radical of the formula II or III, are notesimultaneously hydrogen,excluding elaiophyline, together with an inertcarrier.
 7. A method for treating a patient suffering from ananthelmintic disease which comprises administering to said patient atherapeutic amount of a pharmaceutical composition as claimed in claim4.
 8. A method of treating a patient suffering from an anthelminticdisease which comprises administering to said patient a therapeuticamount of a pharmaceutical composition as claimed in claim
 5. 9. Amethod of treating a patient suffering from an anthelmintic diseasewhich comprises administering to said patient a therapeutic amount of apharmaceutical composition as claimed in claim 6.